Effects of Testosterone on Brain Function on Elderly Men

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This proposal is being submitted in response to NIA PAR 03-056. It is being submitted under the topic "Improve Quality of Life of Older People," guideline 11, Intervention Studies. In men, testosterone (T) levels decline by approximately 50% from ages 30 to 80 and a majority of men over age 70 can be classified as hypogonadal. This progressive loss of T with age in men, often called the "andropause", may have significant cognitive consequences. Indeed, among men with suspected andropause, memory loss is the third most commonly reported symptom. Both epidemiologic and intervention studies highlight the importance of T in maintaining cognitive function. Despite the high morbidity associated with T loss, there have been few studies specifically investigating the neurocognitive effects of T in elderly men. The long term goal of this program of research is to investigate the effects of steroid hormones on cognitive and brain aging. To that end, the specific objective is to investigate the effects of T on spatial memory and functional brain activation in hypogonadal men. Sixteen men will participate in a randomized, placebo-controlled, T intervention study. The principal outcome measures will be behavioral performance on virtual reality tests of spatial navigation and standardized tests of cognitive function. In addition, to assess the neural basis of T action, brain activation will be assessed by functional MRI during a virtual reality spatial memory task. Our central hypothesis is that T replacement will prove beneficial for neurocognitive function in elderly men. Specifically, we hypothesize that T supplementation will increase activation in the hippocampal and parahippocampal system supporting human spatial memory. This proposal is unique in its approach in that it adopts a virtual reality navigation task to assess cognitive and brain function in hypogonadal men. This task serves as an excellent neurocognitive probe to evaluate the hypotheses as it elicits brain activation and age-related changes in those specific neural systems that are demonstrably sensitive to T action. The proposed research is significant in that it will provide us with a detailed account not only of the cognitive systems modulated by T, but also provide us with a putative neural explanation of those same effects. Ultimately, this work will prove essential in the development of intervention strategies to prevent or ameliorate cognitive decline among at-risk elderly individuals.